USP18 Recruits USP20 to Promote Innate Antiviral Response Through Deubiquitinating STING/MITA

Overview

Journal Cell Res

Specialty Cell Biology

Date 2016 Nov 2

PMID 27801882

Citations 71

Authors

Man Zhang

Meng-Xin Zhang

Qiang Zhang

Gao-Feng Zhu

Lei Yuan

Dong-Er Zhang

Qiyun Zhu

Jing Yao

Hong-Bing Shu

Bo Zhong

Affiliations

Soon will be listed here.

Abstract

STING (also known as MITA) mediates the innate antiviral signaling and ubiquitination of STING is key to its function. However, the deubiquitination process of STING is unclear. Here we report that USP18 recruits USP20 to deconjugate K48-linked ubiquitination chains from STING and promotes the stability of STING and the expression of type I IFNs and proinflammatory cytokines after DNA virus infection. USP18 deficiency or knockdown of USP20 resulted in enhanced K48-linked ubiquitination and accelerated degradation of STING, and impaired activation of IRF3 and NF-κB as well as induction of downstream genes after infection with DNA virus HSV-1 or transfection of various DNA ligands. In addition, Usp18 mice were more susceptible to HSV-1 infection compared with the wild-type littermates. USP18 did not deubiquitinate STING in vitro but facilitated USP20 to catalyze deubiquitination of STING in a manner independent of the enzymatic activity of USP18. In addition, reconstitution of STING into Usp18 MEFs restored HSV-1-induced expression of downstream genes and cellular antiviral responses. Our findings thus uncover previously uncharacterized roles of USP18 and USP20 in mediating virus-triggered signaling and contribute to the understanding of the complicated regulatory system of the innate antiviral responses.

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References

Qin Y, Zhou M, Hu M, Hu Y, Zhang J, Guo L . RNF26 temporally regulates virus-triggered type I interferon induction by two distinct mechanisms. PLoS Pathog. 2014; 10(9):e1004358. PMC: 4177927. DOI: 10.1371/journal.ppat.1004358. View

Xu L, Wang Y, Han K, Li L, Zhai Z, Shu H . VISA is an adapter protein required for virus-triggered IFN-beta signaling. Mol Cell. 2005; 19(6):727-40. DOI: 10.1016/j.molcel.2005.08.014. View

Wu J, Chen Z . Innate immune sensing and signaling of cytosolic nucleic acids. Annu Rev Immunol. 2014; 32:461-88. DOI: 10.1146/annurev-immunol-032713-120156. View

Zhong B, Liu X, Wang X, Liu X, Li H, Darnay B . Ubiquitin-specific protease 25 regulates TLR4-dependent innate immune responses through deubiquitination of the adaptor protein TRAF3. Sci Signal. 2013; 6(275):ra35. PMC: 5763475. DOI: 10.1126/scisignal.2003708. View

Donley D . TORCH infections in the newborn. Semin Neurol. 1993; 13(1):106-15. DOI: 10.1055/s-2008-1041114. View

Ritchie K, Hahn C, Kim K, Yan M, Rosario D, Li L . Role of ISG15 protease UBP43 (USP18) in innate immunity to viral infection. Nat Med. 2004; 10(12):1374-8. DOI: 10.1038/nm1133. View

Ketscher L, Hannss R, Morales D, Basters A, Guerra S, Goldmann T . Selective inactivation of USP18 isopeptidase activity in vivo enhances ISG15 conjugation and viral resistance. Proc Natl Acad Sci U S A. 2015; 112(5):1577-82. PMC: 4321242. DOI: 10.1073/pnas.1412881112. View

Chiu Y, MacMillan J, Chen Z . RNA polymerase III detects cytosolic DNA and induces type I interferons through the RIG-I pathway. Cell. 2009; 138(3):576-91. PMC: 2747301. DOI: 10.1016/j.cell.2009.06.015. View

Li Y, Chen R, Zhou Q, Xu Z, Li C, Wang S . LSm14A is a processing body-associated sensor of viral nucleic acids that initiates cellular antiviral response in the early phase of viral infection. Proc Natl Acad Sci U S A. 2012; 109(29):11770-5. PMC: 3406844. DOI: 10.1073/pnas.1203405109. View

10.

Zhang Z, Yuan B, Bao M, Lu N, Kim T, Liu Y . The helicase DDX41 senses intracellular DNA mediated by the adaptor STING in dendritic cells. Nat Immunol. 2011; 12(10):959-65. PMC: 3671854. DOI: 10.1038/ni.2091. View

11.

Holm C, Rahbek S, Gad H, Bak R, Jakobsen M, Jiang Z . Influenza A virus targets a cGAS-independent STING pathway that controls enveloped RNA viruses. Nat Commun. 2016; 7:10680. PMC: 4762884. DOI: 10.1038/ncomms10680. View

12.

Ritchie K, Malakhov M, Hetherington C, Zhou L, Little M, Malakhova O . Dysregulation of protein modification by ISG15 results in brain cell injury. Genes Dev. 2002; 16(17):2207-12. PMC: 186669. DOI: 10.1101/gad.1010202. View

13.

Sun L, Wu J, Du F, Chen X, Chen Z . Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway. Science. 2012; 339(6121):786-91. PMC: 3863629. DOI: 10.1126/science.1232458. View

14.

Zhu M, Zhao H, Liao J, Xu X . HERC2/USP20 coordinates CHK1 activation by modulating CLASPIN stability. Nucleic Acids Res. 2014; 42(21):13074-81. PMC: 4245974. DOI: 10.1093/nar/gku978. View

15.

Knobeloch K, Utermohlen O, Kisser A, Prinz M, Horak I . Reexamination of the role of ubiquitin-like modifier ISG15 in the phenotype of UBP43-deficient mice. Mol Cell Biol. 2005; 25(24):11030-4. PMC: 1316970. DOI: 10.1128/MCB.25.24.11030-11034.2005. View

16.

Takeuchi O, Akira S . Pattern recognition receptors and inflammation. Cell. 2010; 140(6):805-20. DOI: 10.1016/j.cell.2010.01.022. View

17.

Li X, Wu J, Gao D, Wang H, Sun L, Chen Z . Pivotal roles of cGAS-cGAMP signaling in antiviral defense and immune adjuvant effects. Science. 2013; 341(6152):1390-4. PMC: 3863637. DOI: 10.1126/science.1244040. View

18.

Sun W, Li Y, Chen L, Chen H, You F, Zhou X . ERIS, an endoplasmic reticulum IFN stimulator, activates innate immune signaling through dimerization. Proc Natl Acad Sci U S A. 2009; 106(21):8653-8. PMC: 2689030. DOI: 10.1073/pnas.0900850106. View

19.

Yin Q, Tian Y, Kabaleeswaran V, Jiang X, Tu D, Eck M . Cyclic di-GMP sensing via the innate immune signaling protein STING. Mol Cell. 2012; 46(6):735-45. PMC: 3697849. DOI: 10.1016/j.molcel.2012.05.029. View

20.

Kawai T, Takahashi K, Sato S, Coban C, Kumar H, Kato H . IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction. Nat Immunol. 2005; 6(10):981-8. DOI: 10.1038/ni1243. View